Conventional drugs used in the treatment of autoimmune diseases and graft/transplantation rejection, such as cyclosporin A, corticosteroids, azathioprine, polyclonal anti-lymphocyte globulins and monoclonal T cell antibodies are somewhat effective in electing an immunosuppressive response. However, their highly toxicity profiles frequently limit their clinical benefit. Thus, the treatment of autoimmune diseases, graft/transplantation rejection and other maladies requiring immunosuppression with agents having low-toxicity profiles remains a major clinical problem.
The use of monoclonal anti-IL2 receptor antibodies in combination with cyclosporin A has been reported. See, Diamantstein, T, et al., (1986) Immunobiol. 1:391-399; Kupiec-Weglinski, J. W., et al., (1988) Transplant Proc 20:207-216 and Hancock, W. W., et al., (1990), Transplantation 49:416-421. The use of bromocriptine in combination with cyclosporin A (Carrier, M., et al., (1990), Ann. Thorac. Surg. 9:129-32) and thalidomide in combination with cyclosporin A (Tamura, F., et al., (1990) transplantation 49:20-25) has also been reported.
Non-specific suppressor cell inducing compounds are agents which induce the production of a population of natural suppressor cells which do not have the characteristics of mature T cells, B cells, macrophages or natural killer cells and are therefore of the null or non-specific phenotype. Natural suppressor cells are capable of inhibiting a variety of immune responses in vivo.
The immunosuppressive activity associated with total lymphoid irradiation (TLI) has been attributed to the generation of a population(s) of natural suppressor cells. See, Strober, S., (1984) Ann. Rev. Immun. 2:219 and Maier, T., et al., (1986), Immunol. Today 7:312. The use of TLI as part of a combination treatment with cyclosporine and either cyclophosphamide (See, Yamaguchi, Y., et al., (1990), Transplantation 49:13-17) or splenectomy (See, Miyamura, K., et al., (1988), Bone Barrow Transplantation 3:457-461) has been reported.
Classes of compounds known to induce NS suppressor cells include N-amino alkyl azaspirogermanium alkanes (See, e.g., Badger, A., et al., (1985), Immunopharm. 10:201 and DiMartino, M. J., et al., (1986), J. Pharm. Exp. Ther. 236:103) and N-amino alkyl azaspiro alkanes (See, e.g., Badger, A., et al., (1989), Int. J. Immunopharmac. 11:839-846 and European Patent Application Publication Number 0310321 A2).
It has now been discovered that combining a non-specific suppressor cell inducing compound with cyclosporin A increases immunosuppressive activity in vivo to an extent beyond which either compound achieves alone or would be expected to achieve when combined.